Sphingosine 1-phosphate (S1P) is derived from sphingosine, which provides the backbone to all sphingolipids. Phosphorylation of sphingosine, a metabolite of the pro-apoptotic lipid ceramide, to S1P, is mediated by lipid kinases called sphingosine kinases (SphK). There are two SphK isoenzymes: SphK1 or SphK2. SIP may be reversibly deactivated through dephosphorylation by several phosphatases or irreversibly deactivated by S1P lyase. S1P is produced intracellularly in organelles and the plasma membrane and then secreted. The newly generated S1P is then secreted and is bound extensively by albumin and other plasma proteins. This provides a stable reservoir in extracellular fluids, presumably at higher total concentrations than in tissues, and rapid delivery to cell surface receptors. SIP, via its five cognate G-protein coupled receptors (GPCRs), S1P1-5 Rs, regulates diverse biological functions, including inflammatory responses, cell proliferation, apoptosis, cell migration, lymphocyte trafficking and cell senescence. Thus, coordinated activities of biosynthetic and biodegradative enzymes help maintain and regulate concentrations of SIP in the range required for physiological activities.
SIP has been shown to be an important mediator of angiogenesis and tumorigenesis. One way to modulate SIP levels is to target SphK, and thereby affect biosynthesis of SIP. SphK1 has been shown to stimulate proliferation in vitro, and is tumorigenic in vivo. It also imparts resistance to radiotherapy and chemotherapy and is elevated in some solid tumors. SphK1 inhibitors have been shown to have anti-cancer effects in vivo. These effects have been attributed to the inhibition of formation of SIP. Further, a monoclonal antibody against SIP reduces progression of or eliminates tumors in murine xenograft and allograft models. Thus, lowering levels of SIP by inhibiting SphK or by an SIP-specific antibody has anti-tumorigenic effects.
Since many, if not all effects of SIP are mediated by five GPCRs, an alternative approach to cancer therapy may be inhibition of SIP receptors. Of the five known SP receptors, S1P1R has been shown to play an important role in vascular permeability and S1P1R knock-out mice have an embryonic lethal phenotype. Furthermore, there is increasing evidence for cross-talk between S1P1R and other growth factor receptors such as PDGFR. Thus, S1P1 receptor antagonists have the potential to offer clinical benefit as anti-cancer therapeutics.